While acellular vaccines are inevitably safer than vaccines based on whole organisms, a fully effective vaccine cannot normally be made from a single isolated constituent of a microorganism, and it is now clear that this is because of the need to activate more than one cell type to initiate an immune response. One consequence of this insight has been the development of conjugate vaccines.
However, even conjugate vaccines are not usually strongly immunogenic on their own. Most of them require the addition of adjuvants: substances that enhance immunogenicity of antigens. It is thought that most, if not all, adjuvants act on antigen-presenting cells (APCs) and reflect the importance of these cells in initiating immune responses. H. influenzae polysaccharides, for example, have been conjugated to tetanus toxoid because infants are vaccinated routinely with this protein and their T cells are already primed against it.
Tetanus toxin has been studied in detail. For example, see Umland T. C. et al, Nature Structural Biology, Vol. 4 No. 10 1997. A transport mechanism is exploited by the toxin for delivery to its cytotoxic target within the central nervous system. The receptor binding subunit of tetanus toxin plays a dominant role in this delivery process. This receptor binding subunit is known as HC and is composed of the 50,000 Mr fragment from the C-terminal end of the heavy chain of tetanus toxin. Historically, 50,000 Mr fragment has been termed the Fragment C (FrC). Isolated FrC retains the capability of being transported to the CNS in a manner similar to that of the intact tetanus toxin.
Tetanus toxoid has been used as a carrier protein for inducing immune responses against peptides (Herrington et al, 1992 J. Immunol. 149:717). There is considerable information available on immune responses against tetanus toxoid and the epitopes recognized by human CD4+ T cells (Valmori et al, 1992 J. Immunol. 149:717), as well as the mechanisms involved in enhancing immunity to added peptides (Panina-Bordignon et al, 1989 Eur. J. Immunol. 19:2237; Kumar 1992 J. Immunol, 148:1499). Fragment C (FrC), the 50 kD carboxy-terminal portion of the heavy chain of tetanus toxin, has been found to induce protective immunity again tetanus toxin which is largely antibody-mediated (Anderson et al, 1996. Infect. and Immun. 64:3168).
Previous work (King, C. A. et al, Nature Medicine, 1998, Vol. 4 p. 1281), jointly authored by a co-inventor of the present invention, describes the use and production of nucleic acid constructs for inducing an immune response in a mammal to a disease antigen present on a malignant B cell in the mammal. The DNA construct directs the expression of a fusion protein which comprises the tumour antigen and the tetanus toxin Fragment C (FrC). Thus, it has already been shown that an immune response to a given antigen can be enhanced by the presence of FrC itself.